Role of miR155 in Leukemogenesis Expression of microRNA genes is consistently altered in liquid and solid malignancies. We have shown that microRNA genes such as miR15 and miR16 function essentially as tumor suppressor genes in B cells and are deleted or underexpressed in chronic lymphocytic leukemia (CLL) with an indolent phenotype. We have also shown that miR15 and miR16 target the BCL2 oncogene. Thus decreased expression of miR-15 and miR-16 leads to BCL2 overexpression, contributing to malignant transformation. On the contrary, other microRNA genes are overexpressed in human malignancies: for example miR155 is overexpressed in aggressive CLLs, in a fraction of Burkitt's lymphomas, in ABC type of diffuse large B cell lymphoma and in several solid tumors. We intend to prove that miR155 is an oncogenic microRNA involved in human cancer and that inhibition of this microRNA can result in the prevention and treatment of miR155 driven malignancies. For this purpose, we have constructed transgenic mice in which we targeted overexpression of miR155 to pre B cells by using the immunoglobulin E5 enhancer. Analysis of these mice indicated the development of aggressive pre B cell neoplasms, signs of which are already detectable 3-4 weeks after birth. We propose: 1) to demonstrate that the overexpression of a single microRNA, miR155, can cause an aggressive malignancy; 2) to demonstrate the involvement of miR155 in human acute lymphoblastic leukemia, and 3) to demonstrate that miR155 antagomiRs can result in the prevention and regression of ALL in leukemic transgenic mice. Thus this study will provide the rationale for the development of a miR based strategy for the prevention and cure of cancers caused by microRNA deregulation. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of a microRNA, miR155, in the pathogenesis of human cancer. This microRNA is overexpressed in several different human cancers. The study will rely on transgenic mice that overexpress this microRNA in their B cells. Since miR155 transgenic mice develop aggressive malignancies, we will test the hypothesis that by inhibiting the expression of this microRNA the malignancies will regress. This will provide the basis for the development of antimiR155 therapies in human cancer.